title: Endothelin 1 stimulates Ca2+-sparks and oscillations in retinal arteriolar myocytes via IP3R and RyR-dependent Ca2+ release.
abstract: OBJECTIVE
  To investigate endothelin 1 (Et1)-dependent Ca(2+)-signaling at the cellular and subcellular levels in retinal arteriolar myocytes.
  
  
  METHODS
  Et1 responses were imaged from Fluo-4-loaded smooth muscle in isolated segments of rat retinal arteriole using confocal laser microscopy.
  
  
  RESULTS
  Basal [Ca(2+)](i), subcellular Ca(2+)-sparks, and cellular Ca(2+)-oscillations were all increased during exposure to Et1 (10 nM). Ca(2+)-spark frequency was also increased by 90% by 10 nM Et1. The increase in oscillation frequency was concentration dependent and was inhibited by the EtA receptor (Et(A)R) blocker BQ123 but not by the EtB receptor antagonist BQ788. Stimulation of Ca(2+)-oscillations by Et1 was inhibited by a phospholipase C blocker (U73122; 10 μM), two inhibitors of inositol 1,4,5-trisphosphate receptors (IP(3)Rs), xestospongin C (10 μM), 2-aminoethoxydiphenyl borate (100 μM), and tetracaine (100 μM), a blocker of ryanodine receptors (RyRs).
  
  
  CONCLUSIONS
  Et1 stimulates Ca(2+)-sparks and oscillations through Et(A)Rs. The underlying mechanism involves the activation of phospholipase C and both IP(3)Rs and RyRs, suggesting crosstalk between these Ca(2+)-release channels. These findings suggest that phasic Ca(2+)-oscillations play an important role in the smooth muscle response to Et1 within the retinal microvasculature and support an excitatory, proconstrictor role for Ca(2+)-sparks in these vessels.
authors.affiliation: Centre for Vision and Vascular Science, Queen's University of Belfast, Institute of Clinical Sciences, The Royal Victoria Hospital, Belfast, Northern Ireland.
authors.forename: James
authors.initials: J
authors.lastname: Tumelty
authors.forename: Kevin
authors.initials: K
authors.lastname: Hinds
authors.forename: Peter
authors.initials: P
authors.lastname: Bankhead
authors.forename: Neil J
authors.initials: NJ
authors.lastname: McGeown
authors.forename: C Norman
authors.initials: CN
authors.lastname: Scholfield
authors.forename: Tim M
authors.initials: TM
authors.lastname: Curtis
authors.forename: J Graham
authors.initials: JG
authors.lastname: McGeown
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018613:Microscopy, Confocal; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012161:Retinal Artery / Q000187:drug effects* / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D014966:Xanthenes / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019332:Endothelin-1; D004791:Enzyme Inhibitors; C409648:Fluo 4; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D014966:Xanthenes; D010738:Type C Phospholipases; D002118:Calcium